Homogonane derivatives

ABSTRACT

13B-(LOWER ALKYL)-B-(6)-HOMOGONENES HAVE BEEN FOUND TO POSSESS PROPERTIES USEFUL FOR FERTILITY CONTROL AND IN THE THERAPY OF MENOPAUSAL PROBLEMS. THEY ARE ALSO USEFUL FOR GROWTH STIMULATION, POSTOPERATIVE RECOVERY AND HEALING OF WOUNDS AND BURNS.

United States Patent 9 Claims ABSTRACT OF THE DISCLOSURE l3/8-(lower alkyl)-B-(6)-homogonenes have been found to possess properties useful for fertility control and in the therapy of menopausal problems. They are also useful for growth stimulation, postoperative recovery and healing of wounds and burns.

This application is a division of application Ser. No. 630,496 filed Apr. 13, 1967 now US. Pat. No. 3,505,393, which is a continuation-in-part of application Ser. No. 603,160 filed Dec. 20, 1966 now US. Pat. No. 3,513,204 which in turn is a continuation-in-part of application Ser. No. 566,730 filed July 21, 1966, and now abandoned.

This invention relates to B-(6)-homogonane derivatives of the formula 5 V 4 6 (ibis I wherein any hydrogen atom bound to. C C14, and/or C is in the u-position; any hydrogen atom bound to C and/or C is in the S-position; R is bound to C and is either p-methyl, fl-ethyl, B-propyl or fl-isopropyl; R is bound to C and is either fi-hydroxy, fl-alkanoyloxy having from 2 to 20 carbon atoms, e.g. acetyloxy, caproyloxy and palmityloxy; or, together with R 0X0; and .1 R is bound to C and is either u-hydrogen; a-(lower 1 alkyl, e.g. a-methyl, a-ethyl, a-propyl, a-isopropyl and u-butyl; a-lower alkenyl), e.g. a-methallyl, a-vinyl and a-allyl; a-(lower alkynyl), e.g. a-propargyl and aethynyl; a-chloroethynyl; a-fiuoroethynyl; or, together with R oxo; Ring A is one of the following:

i and I I R 0 O 0- R O a b c d R is either a hydrogen atom (H), carboxylic acid acyl having from 2 to 4 carbon atoms, e.g. acetyl, propionyl and butyryl or R R is lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; or cycloalkyl having an unsubstituted 5 to 7 membered ring, e.g. cyclopentyl;

Ring B has at least one unsaturated carbon atoms (C Rings C and D areeither saturated or unsaturated;

3,708,541 Patented Jan. 2, 1973 processes and intermediates employed in the preparation thereof and pharmaceutically acceptable compositions containing same.

The unsaturation in the remainder of the structure of compounds I is dependent to some-extent on the saturation of the carbon atoms which form ring A. Preferred compounds wherein ring A is in form a are those which are otherwise saturated, have A, have A or have A preferred compounds wherein ring A is in form b are those which are otherwise saturated, have A or have A and preferred compounds wherein ring A is in either form 0 or form d are those which otherwise are saturated or have A The compounds of this invention are named from the parent steroid hydrocarbon Gonane (or Sterane) The individual rings of the depicted structure are designated, from left to right, A, B, C and D, as indicated in Formula I. In the structures of the compounds to which the present invention is directed there is an additional carbon atom in one of the rings; the compound is thus called a homogonane derivative. The fact that the additional carbon is in the B-ring makes it, more specifically, a B-homogonane. In order to specify that said additional carbon atom is interposed between C and O, (as opposed to, e.g., between C, and C the compounds are designated as B-(6)-homogonanes. In practice it is unnecessary to include the ('6) in the name, but it is understood that all of the subject homosteroids are so restricted. Each of the homosteroids of this invention additionally has at least one double bond; it is therefore a B-(6)homogon- (monoor poly-)ene, hereinafter referred to generically as a B-(6)-homogonene.

Each compound I is unsubstituted in both the 5- and IO-position and is either an optically active isomer or a mixture of two such isomers, including racemates which consist of a levorotary and the corresponding dextrorotary form (enantiomers) in 1:1 proportion. Totally synthetic preparation of compounds I results in racemates which are separated into their enantiomers by resolution according to well-established procedures known to those skilled in the art. Usually only one of the optically active forms exerts useful biological activity, i.e. the form in which C has the same absolute configuration as, e.g., in estrone or in other naturally-occurring steroids. It is thus advantageous to separate said form from its enantiomer to obtain a product having greater activity.

Compounds I are useful in the treatment of female hypogonadism, endometriosis, amenorrhea, dysmenorrhea, functional uterine bleeding, acne, osteoporosis, infertility and habitual abortion. They are also useful in achieving ovulation block, pregnancy maintenance, nitrogen retention, growth stimulation, post-operative recovery, healing wounds and burns lipid shifting and lowering of the blood cholesterol level. They are particularly useful for fertility control and the therapy of menopausal problems. They are also intermediates for preparing compounds with the indicated utilities.

Compounds I are administered to mammals daily (or in long-acting preparation) in standard dosage forms, e.g. i"; tablets or capsules perorally or in oily solutions, emulsions or suspensions subcutaneously or intramuscularly. Daily doses range from 0.001 to 1.2 rug/kg. of body weight, e.g. 0.05 to 80 milligrams.

Each of the pharmaceutically active compounds of this invention may be, e.g., incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to 10 percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water. An exemplary tabletting formulation for the instant active compound is:

Parts Title compound of Example 15 .25 Tragacanth 2. Lactose 89.25 Corn starch 5. Talcum 3. Magnesium stearate 0.5

Alcohol SD-30, q.s. Purified water, q.s.

Among the compounds of the present invention, 3-methxy-l3 (lower alkyl)-B-homogona-1,3,5 10 ,8,14-pentaen-17-ones V are prepared according to Scheme A:

CH3O

III

Z-methoxy-6,7,8,9-tetrahydro 5H benzocyclohepten- S-one [J. Chem. Soc., 990 (1966)] II is reacted with a vinylmagnesiurn halide to yield Z-methoxy-S-vinyl-6,7,8,9- tetrahydro-5H-benzocyclohepten-S-ol III. (Other 2-loweralkoxy counterparts are obtained from corresponding starting materials.) III is subsequently reacted with a 2-(lower alkyl)-cyclopenta-l,3-dione [Bull. Soc. Chim., France, 1036 (1955)] in moderately acid (acetic acidxylene) or basic (triethylenediamine-xylene) media under reflux; this-prepared 3-methoxy-8,14-seco-13-(lower alkyl)-B-homogona-1,3,5 l 0) ,8 [and/ or 9(11)]-tetraene- 14,l7-dione IV is cyclized with acid, e.g. p-toluenesulfonic acid in boiling benzene and hydrochloric acid in methanol, at from 20 to 60, or polyphosphoric acid, to obtain compounds V.

Other compounds of this invention can be prepared from V, by the following modifications or combinations thereof:

Reduction or alkylation of the 17-ox0 group-Scheme B Reduction or hydrogenation of the double bonds in rings B, C, D-Scheme C Demethylation of the 3-rnethoxy group, followed, if desire b e l lqtien 9r apnea-Sche e 19 Reduction of the aromatic ring A by the so-called Birch method, followed by hydrolysis of the thus-formed enol ether-Scheme E Introduction of a A double bond in products obtained according to Scheme E, .by bromination-dehydrobromination (or other dehydrogenation methods) Step b is reduction (by sodium borohydride or lithium aluminum hydride) when R =I-I; it is a reaction with R =MgCl, .R =MgBr, R =Li, R Na or -R ,=K when R is other than H.

Step b is the reversal of step b' 'and is effected, in cases where R =H, by oxidation'methods employing chromicsulfuric acid in acetone (Jones method), chromic acid in pyridine or aluminum-isopropoxide-cyclohexanone (Oppenauer method).

Step b is acylation of the l7 3-hydroxy group.

Scheme 0:

CHaO

R2 QIFWR' OHQO C1130 VII 7 Scheme D:

Step al is demethylation'efiected by, e.g., molten pyridine hydrochloride, boron tribromide or hydrogen bromide.

Step d is alkylation, cycloalkylation or acylation.

Again, it is preferred to select, for steps d and d compounds of the present in ention which. under t e con.

3-cyclopentyloxy-13,6-ethyl-17y3-heptadecanoyloxyl7a-methyl 3-butoxy-17a-chlorethynyl-13fi-ethyl-17fi-octanoyloxy 13p-isopropyl-l7u-fluorethynyl-17 3-nonanoyloxy-3- ethoxy B-homogona-2,5 10) ,8 14) -trien- 1 75-01 3 -methoxy-13fl-methyl 13 p-ethyl-S-methoxy 13-B,17a-diethyl-3-methoxy l7u-ethynyl-3-methoxy-l 3 ,B-methyl 17a-chlorethynyl-l 3y8-ethyl-3 -methox-y B-homogona-2,5( 10) ,8 14) -trien-17-one 13fl-isopropyl-3 methoxy 3 -methoxy-13;8-methyl 17 3-hydroxy-B-h0mogon-4-en-3-one 13 B rnethyl 13/3,17a-diethyl B-homogon-4-ene,-3,17-dione B S-methyl 13 fi-ethyl 1 3 ,9-isopropy1 13,3-propyl B-homogon-4-en-3-one 17ot-a11yl- 1 7fi-decanoyloxy- 1 Zip-methyl 17-afluorethynyl-13,3-isopropyl417fi-pentadecanoyloxy 17/3-hydroxy-B-homogona-4,8 (14)-dien-3 -one 13B-methyl I 1 3 8-ethyl-17a-ethynyl 13B-ethy1-17a-propyl B-homogona-4,8 14) -diene-3, 17-dione 1 3 B-methyl 1 3B-ethy1 1 Bfl-propyl 13 B-isopropyl 175-hydroxy-B-homogona-4,8( 14 ,9-trien-3-one 1 3 fl-methyl 1 3 B-ethyl- 17 a-ethynyl 13 fl-ethyl- 17a-propynyl 17a-ethyl-13fi-methyl 17 a-fiuorethynyl-l 3 p-methyl IBB-isopropyl B-homogona-4, 8( 14) ,9-triene-3 17 -dione l3fl-methyl 13B-ethyl 13 B-isopropyl 1 3fl-propyl B-homogona-4,8 14) ,9-trien-3-one 17u-butyl-17fl-dodecanoyloxy-13,3-isopropyl l7-u-ethynyll SB-isopropyl-l 7poctadecanoyloxy 17/8-hydroxy B-homogona-4,9-dien-3-one 13 fl-methyl 13 B-ethyl B-homogona-4,9-diene-3,17-dione 13 8-ethyl 1 3 fi-isopropyl B-homogona-4,9-dien-3-one 13B-ethyl-17a-isopropyl-17B-undecanoyloxy 1 3 8 methyl-1 7fi-nonadecanoyloxy-17a-vinyl 17 fi-hydroxy-B-homogon-S 10) -en-3-one 13 B-methyl 13 B-ethyl 17m-ethynyl-13B-methyl 17a-chlorethynyl-13 B-isopropyl B-homogon-S 10) -ene-3 ,17-dione Bit-ethyl 1 3,8-methyl 13-,8-isopropyl I B:homogon-(10)-en-3-one 17a-isopropyl-13p-methyl-17.,8-tridecan0yloxy -1713-hydroxy-B-homogona-5 ,8 14)-dien-3-one 13,8-methyl v v 13p-ethyl- 17 a-ethynyl B-homogona-S 10) ,8( 14)-diene-3,17-dione B S-methyl 13p-ethyl 13fl-propyl l SB-isopropyl All compounds within the scope of this invention are prepared from available, i.e. compounds which are either known per se or are prepared from known compounds by analogy procedures within the skill of the art, starting materials and/ or intermediates.

The examples which follow are merely illustrative of the invention, all temperatures being in degrees centigrade, the parts and percentages being by weight unless otherwise specified and the relationship between parts by weight and parts by volume being the same as that between the kilogram and the liter.

Unless stated otherwise, reaction mixtures obtained as specified in the examples are worked up in the following manner: the mixture obtained from the chemical reaction is distributed between water and a solvent, e.g. benzene, ethyl acetate and chloroform, which is not miscible with water. (If solvents miscible with water are used in the reaction, they can be partially or totally removed by vacuum evaporation from the reaction mixture prior to distribution.) The aqueous phase is then separated and further extracted with the specified solvent until practically all of the desired organic product is collected in the solvent. The unified organic solution is then washed with water or aqueous solutions, e.g. (aq.) sodium hydrocarbonate and dilute (aq.) hydrochloric acid, to remove, if feasible, side products. After drying over an anhydrous salt, e.g. sodium sulfate, the solution is evaporated in vacuo to give the crude product as a residue, which is purified by crystallization, recrystallization, chromatoggraphy or high-vacuum distillation. All of these are wellknown operations to the skilled in the art.

EXAMPIJE l Z-methoxy-5-vinyl-6,7,8,9-tetrahydro-5H- benzocyclohepten-S-ol CHaO Prepare vinyl magnesium bromide from 6.7 parts of magnesium turnings and 37.0 parts of vinyl bromide in parts by volume of tetrahydrofuran (THF). Add (over a period of 30 minutes and at 30) to the resultant vinyl magnesium bromide a solution of 14.7 parts of 2- methoxy-6,7,8,9-tetrahydro 5H benzocyclohepten 5- one in 150 parts by volume of THF. Maintain the resulting mixture at room temperature (20) for 16 hours. After cooling to 5, add dropwise thereto 75 parts by volume of a saturated aqueous ammonium chloride solution and work up the thus-produced organic layer with ethyl acetate. The title compound is thus obtained as an oil.

EXAMPLE 2 (a) 3-methoxy-13-methyl-8,14-seco-B-homogona- 1,3,5 10),9( l 1 )-tetraene-14, 17-di0ne CHaO Add (over a period of 3 /2 hours) a solution of 21.8 parts of 2 methoxy-5-vinyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-S-ol in 150 parts by volume of xylene to a mixture of 9.6 parts of Z-methylcyclopentane-1,3'dione, 0.75 part of triethylene diamine and 450 parts by volume of xylene refluxing under a Dean-Stark water trap. After refluxing for an additional six hours, cool the mixture to room temperature, wash same with 5% (aq.) potassium hydroxide solution, then wash with water, dry over sodium sulphate and evaporate to a dark viscous oil; obtain the pure title compound by chromatography over silica gel.

(b) 3-methoxy-13,8-methyl-B-homogona-1,3,5( 8,14-pentaen-17-one (c) 3 -methoxy- 1 SB-methyLB-homogona- 1,3,5 10

8-tetraen-17-one Catalytically hydrogenate 3-methoxy 13,3 methyl-B- homogona-l,3,5(10),8,14-pentaen-l7-one under the conditions described in Example 3(b) to obtain the title compound as an oil; the oxime, prepared in the usual way, has a M.P. of 183, dec.

EXAMPLE 3 (a) 3-methoxy-13B-methyl-B-homogona-1,3-5( 10) 8,14-pentaen-17fl-ol Cool to -30 a suspension of 2.06 parts of 2(b) in 140 parts by volume of methanol. Add to the suspension (with stirring) 0.3 part of sodium borohydride. Continue stirring for 4 hours while maintaining the same temperature. Add acetic acid and water to the reaction mixture, filter and wash with water and then dry at room temperature to separate crystalline title compound (decom- CHaO position at 54). (To characterize, prepare the 17fi-aeetate with acetic anhydride in pyridine; M.P. 139 to 142.)

(b) 3-methoxy-13fl-methyl-B-homogona-l,3,5 l 0) ,8- tetraen- 1 718-01 (in L K Add 0.5 part of 3(a) to 0.15 part of palladized calcium carbonate prehydrogenated under 10 parts by volume of dioxane. Stir under an atmosphere of hydrogen and at room temperature until one mole of hydrogen is consumed. Filter off the catalyst and evaporate the filtrate to dryness. Triturate the residue in petroleum ether to obtain the title compound M.P. 108 to 111; acetate M.P. 103 to 106.

(c) 3-methoxy-13/3-methyl-B-homogona-L3 ,5 l0

trien- 17,8-01

Add portionwise (with stirring) 2.2 parts of sodium to 2.2 parts of 3(b) in 150 parts by volume of liquid ammonia, 40 parts by volume of THF and 15 parts by volume of aniline.

After stirring for twenty minutes add ammonium chloride, diethyl ether and water to the resultant. Separate and dry the ethereal layer and then evaporate same to obtain the title compound; acetate M.P. 117 to 120.

(d) 3-methoxy-13fi-methyleB-homogona-1,3,5(10)- trien-17-one CHa Q WQ Add to the stirred mixture of 3 parts of 3(c) and 6 parts of anhydrous magnesium sulfate in parts by volume of acetone, 3.6 parts by volume of Jones Reagent (8 N chromic acid-sulfuric acid solution). After 2 minutes at room temperature, add thereto 9 parts by volume of isopropyl alcohol and 6 parts of sodium hydrocarbonate. Evaporate the mixture and distribute the residue between diethylether and water. Evaporate the dried gthereal layer to obt in the title p du t. M'P- 8 o 1 3 (e) l 3,8-methyl-B-homogona-1,3,5 10) ,S-tetraene- 3,17fl-diol CH; OH

To a clear solution of 14.5 parts of 3(b) in 1000 parts by volume of liquid ammonia, 700 parts by volume of dry THF and 300 parts'by volume of aniline, add 4.0 parts of lithium metal. After six hours add 35 parts of ammonium chloride to the resultant; then add thereto 500 parts by volume of water. Allow the ammonia to evaporate. Then acidify the resulting mixture to pH by the addition thereto of 400 parts by volume of concentrated hydrochloric acid. Isolate the steroidal material (14.5 parts of yellow foam) by extraction with diethylether. Crystallize the title com pounds, M.P. (184)186 to 188.5", from the ether extract with 100 parts by volume of benzene. [The diacetate, M.P. 135 to 138", is prepared in the standard way.]

Evaporate to dryness the benzene mother liquor and redissolve the obtained residue in 50 parts by volume of 95% ethanol. On maintaining the resultant at 6, 3(c), M.P. 79 to 109, precipitates. [The acetate of 3(c), M.P. 117 to 120", is prepared in the standard way.]

(f) 3-hydroxy-13fl-methyl-B-homogona-1,3,5(10),8- tetraenl7-one (g) 17a(2-butyn-l-yl)-13fl-methyl-B-homogona-1,3, (10),8-tetraene-3,17fl-diol ---CHz-CE C-C Ha Following the procedure of Example 4(b), but replacing compound 4(a) with an equivalent of compound 3(f), results in the preparation, in similar manner, of the title compound, M.P. 193 to 197.

14 (h) 17a-methallyl-13fl-methyl-fi-homogona-1,3,5 (10),8- tetraene-3,17p-diol 0H CH:

--oH2- =CH2 Maintain a melt of 0.30 part of 3(d) and 2.2 parts of pyridine hydrochloride at 210 for 40 minutes. After cooling the resulting melt to room temperature, add water and diethylether thereto. Wash the ethereal layer several times with 2 hydrochloric acid and water; dry same and evaporate to obtain the title compound.

(b) 1 7a- Z-butyn-l -yl -1 3fl-methyl-B-homogona- 1,3,5 10) -triene-3, 17fi-diol Mix a solution of 0.970 part of 4(a) in 20 parts by volume of benzene with a solution of 0.015 part of ptoluenesulfonic acid in 8 parts by volume of benzene (both azeotropically dried). Admix 3.0 parts by volume of dihydropyran with the resultant. After 18 hours at 25, pass the resulting admixture through a column of 20.0 parts of Merck reagent alumina, and subsequently wash the column with about 200 parts by volume of benzene. Evaporate the benzene eluates to obtain the S-tetrahydropyranylether, M.P. ()103 to 116, of 4(a).

To a refluxing Grignard mixture (prepared, in the usual manner, from 0.665 part of magnesium turnings and 3.2 parts of butynyl bromide under 10 parts by volume of diethylether) add a solution of said 3-tetrahydropyranylether of 4(a) in 10 parts by volume of THF. After ten minutes of reflux, cool the refluxed material to 5 and then decompose same by slowly adding thereto 5.0 parts by volume of saturated (aq.) ammonium chloride solution. Thereafter add to the resultant 1.0 part of anhydrous sodium sulfate. Filter 011 the solids, wash same with THE, combine the filtrate and washings and evaporate the obtained combination to dryness. Dissolve the residue (yellow gum) in 10 parts by volume of benzene, wash the obtained solution with water before adding same to a solution of 0.020 part of p-toluenesulfonic acid in 50 parts by volume of 1:1 acetone/water.

After maintaining for two hours at room temperature, concentrate the resultant admixture in vacuo to 20 parts by volume and then extract same with benzene to obtain a foam. Crystallize the foam from diethyl ether (3 parts by volume)-petroleum ether (20 parts by volume) to obtain the title compound, M.P. (l68)-169 to 172".

Following the procedure of Example 4(b), but replacing the butynyl bromide with an equivalent of methallyl chloride, results in the preparation, in similar manner, of 17 a-methallyl-l3B-methyl B homogona-l,3,5( 10)-triene- 3,17p-diol, M.P. 85 to 87 (dec.).

EXAMPLE 5 3-methoxy-13fl-methyl-l7u-ethnyl-B-homogona- 1,3,5 (10),8-tetraen-17/3-ol H CH3 "CECH Pass acetylene through a solution of 0.1 part of lithium and 20 parts by volume of ethylene diamine for 1 hour. Then, at room temperature, and over a period of 30 minutes, add to the resultant a tetrahydrofuran (6 parts by volume) solution of 0.2 part of 3-methoxy-13fl-methyl- B-homogona-1,3,5(l0),8-tetraen-17-one. After two hours add thereto 1 part of ammonium chloride and then 100 parts by volume of water. Extract the thus-prepared mixture with diethyl ether. Wash the ethereal extract with 2% hydrochloric acid and then with water; dry and evaporate the resultant to obtain the title compound; M.P., after crystallization from methanol-petroleum ether: 139 to 141.

EXAMPLE 6 (a) 3-methoxy-13/3-methyl-B-homogona- 1,3,5 (-10),8 14) -tetraen-l7-fi ol CHQO To a mixture consisting of 2300 parts by volume of distilled liquid ammonia, 452 parts by volume of aniline, 820 parts by volume of tetrahydrofuran and 34.8 parts of 3-methoxy-l3fi-methyl B homogona-l,3,5(l0),8,14- pentaen-17fl-ol, within 30 minutes, 8.9 parts of lithium metal. After hours at refluxing ammonia temperature, add 8.7 parts of ammonium chloride and allow the ammonia to escape. Work up the mixture with diethyl etherbenzene 1:1, remove the aniline by subsequent washings with 2 N hydrochloric acid. Evaporate to dryness the washed and dried ether-benzene solution and dissolve the residue (35 parts) in a mixture of 175 parts by volume of acetic anhydride and 525 parts by volume of dry pyridine. After overnight at room temperature, pour the mixture on ice (300 parts); filter the crude acetate of the title product, which separates crystalline, M.P. 89 to 94, and wash same with methanol. Stir the acetate with a mixture of 1350 parts by volume of methanol and 550 parts by volume of 5% sodium hydroxide solution at room temperature for 18 hours, filter and wash with water to obtain the title product, M.P. 96 to 99, M.P. of the (pure) acetate 91 to 93.5".

1 6 (b) 3-methoxy-13B-methyl B-homogona-1,3,5(l0),8, (14) -tetraenl7-one CHa omo

To a solution of 3.0 parts of (a) in parts by volume of acetone, add 3.6 parts by volume of 8 N chromic acid solution. The temperature rises from 25 to, 36 within 5 minutes. Add 12 parts by volume of isopropyl alcohol and 6.0 parts of sodium hydrocarbonate, filter the mixture and thoroughly wash the solids with warm chloroform. Evaporate the combined filtrates and washings to dryness and dissolve the residue in benzene To a Grignard mixture prepared from 0.073 part of magnesium metal and 0.426 part of methyl iodide in 10 parts by volume of diethylether, add a solution of 0.142 part of (a) in diethylether. Distill off the ether and maintain the residue (protected by "a nitrogen atmosphere) at for 45 minutes. Cool the resultant to room temperature by adding ice and water thereto. Then acidify to pH 1 with 6 N hydrochloric acid. The title compound, M.P. 98 to 120 (foaming), precipitates and is isolated by filtration.

(d) 3-hydroxy-13fl-methyl- B-homogona-1,3,5(10),8

(14)-tetr'aen-17-one Following the procedure of Example 3(f), but replacing compound 3(e) with 2.87 parts of 6(c), results in the preparation of the title compound, M.P. 198 to 208 (dec.).

(e) 17a-methallyl-13 3-methyl-B-homogona-1,3,5 (10,)

17 Following the procedure of Example 4(b), but replacing compound 4(a) with an equivalent of compound 6(d) and replacing the butynyl bromide with an equivalent of methallyl chloride, results in the preparation, in similar manner, of the title compound, which remains as a foam. The foam is characterized by the NMR spectrum of its B-acetate derivative: C-methyl peaks at 69.0, 101 to 101.5

and 136 cps. (60 MC, CDCl EXAMPLE 7 3-methoxy-1SB-methyl-l7a-ethyl-B-homogona 1,3,5,(10),8(14)-tetraen-17B-ol CH3 C Add, to a Grignard mixture prepared from 1.23 parts of magnesium metal and 5.95 parts of ethyl bromide in 10 parts by volume of diethyl ether, 3.0 parts of 3-methoxy-13B-methyl-B-homogona-1,3,5 10 ,8 14) tetraen- 17-one dissolved in 75 parts by volume of xylene. Distill off the ether and reflux the mixture for 18 hours. After cooling, add saturated (aq.) ammonium chloride solution and extract product with chloroform. M.P., after recrystallization from isopropyl alcohol, 127

EXAMPLE 8 3-methoxy-13 8-methyl-17u-ally1-B-homogona- 1,3,5 10),8 14) -tetraen-l7B-ol To a Grignard mixture (prepared in the usual way from 2.91 parts by volume of allyl bromide, 0.740 part of magnesium and 50 parts by volume of diethyl ether) add a solution of 1.2 parts of 3-methoxy-13/3-methyl-B-homogona-l,3,5(10),8(14)-tetraen-17-one in 10 parts by volume of benzene-diethyl ether (1:1). After 30 minutes, add 60 parts by volume of xylene to the resultant and raise the temperature of the mixture, within hours, to 120 while allowing the lower-boiling solvents to distill off. After cooling to room temperature, add 120 parts by volume of saturated ammonium chloride solution and wash the organic layer with subsequent portions of water. Dry over sodium sulfate and evaporate off the dried solution to obtain a red gum. Chromatograph the red gum on a silica gel column to obtain the title compound which, after crystallization from isopropyl alcohol, has the M.P. of 134 to 136.

EXAMPLE 9 (a) 3-methoxy-13fi-methyl-B-homogona- 2,5(),8(14)-trien-17p-ol CHa To a mixture of 175 parts by volume of liquid ammonia, 45 parts by volume of tert.-butanol, 450 parts by volume of tetrahydrofuran and 5.0 parts of 3-methoxy- 13,8 methyl-B-homogona-1,3,5(10),8(14)-tetraen- 17B- ol, add 0.90 part of lithium. After 1 hour at refluxing ammonia temperature, add an additional quantity of 0.45 part of lithium. After 4 hours at the same temperature add 50 parts by volume of methanol and evaporate the ammonia by the aid of a water aspirator. Thereafter add 300 parts by volume of Water and then wash the mixture with water before concentrating in vacuo until crystallization of the product starts. Filter and dry over phosphorus pentoxide to obtain the title product, M.P. 83 to 92.

(b 17,6-hydroxy- 13 B-methyl-B-homogona- 5(10),8(14)-dien-3-one Stir a mixture of 2.8 parts of 3-methoxy-13fl-methyLB- homogona 2,5(10),8(14) trien 17B 01 in 50 parts by volume of acetic acid and 10 parts by volume of water at room temperature. After 25 minutes extract the mixture with chloroform. Wash the chloroform solution with sodium hydrocarbonate solution and water; then dry same over sodium sulfate and evaporate to obtain the title product. Crystallize the title compound from petroleum Treat a solution of 0.3 parts of 17;3-hydroxy-13 6- methyl B homogona 5(10),8(l4) dien 3 one in 40 parts by volume of pyridine at 5 with 3.5 parts of pyridinium bromide perbromide. After 5 minutes dilute the mixture with water and filter the resulting precipitate. Then wash the precipitate with water. Dissolve the thusobtained crude dibromide in 200 parts by volume of pyridine and allow the resulting solution to stand at room temperature for 2 hours. Then concentrate the mixture to about 10 parts by volume in vacuo, dilute the concentrate with water and obtain the crude title product by extracting the resulting mixture with methylene chloride, drying the extract and evaporating the methylene chloride solution therefrom. Crystallize the title compound from diethyl ether.

(d) 13[3-methyl-B-homogona-4,8(14),9-trien-3,17-dione 0 CH3 I Add to a stirred mixture of 30 parts of 17/3-hydroxymethyl B homogona 4,8(14),9-trien-3-one and 60 parts of anhydrous magnesium sulfate in 1500 parts by volume of acetone, 36 parts by volume Jones Reagent (8 N chromic acid-sulfuric acid). After minutes add 90 parts by volume of isopropyl alcohol, followed by 60 parts of sodium hydrocarbonate. Evaporate the acetone and distribute the residue between chloroform and water. Evaporate the dried chloroform solution and crystallize the residue to obtain the title compound.

EXAMPLE (a) 17a-ethyl-3 -methoxyl 3/3-methyl-B-homogona- 2,5( 10 ,8 14 -trien-17B-ol OH CH3 iorns Add, at -60", 4 parts of lithium to a solution of 1.10 parts of 3 methoxy 17a ethyl 135 methyl-B- homogona 1,3,5(10),8(l4) tetraen 17/3 01, 200 parts by volume of tetrahydrofuran (THF) and 400 parts by volume of liquid ammonia. After stirring the resultant for 30 minutes, add 50 parts by volume of ethanol dropwise thereto. Allow the ammonia to evaporate from the mixture. Then add water thereto to precipitate the title compound. Filter the precipitate and recrystallize same to obtain purified'title compound.

(b) 17a-ethyl- 17B-hyd roxy- 1 3 ,B-methyl-B-homogona- 4, 8 14 -dien-3-one Add dropwise 15 parts by volume of 6 N hydrochloric acid to a solution of 0.8 part of (a) in 40 parts by volume of 1:1 THF/ methanol. After maintaining the resultant for 60 minutes at room temperature, dilute same with water and extract through chloroform to obtain the title compound.

EXAMPLE 1 l (a) 3-methoxy-13B-methyl-B-homogona-2,5(10)- dien-17 3-01 Add 13 parts of lithium to a solution of 22.3 parts of 3 methoxy 135 methyl-B-homogona-l,3,5(10)-trien- 175-01, 700 parts by volume of liquid ammonia and 450 parts by volume of THF. Treat the resultant dropwise with 145 parts by volume of ethanol. Evaporate the ammonia and then add ethyl acetate to the remainder. Wash and dry the ethyl acetate layer before evaporating same to dryness. Recrystallize the residue to obtain the title compound.

2%) (b) Z-methoxy-l3B-methyl-B-homogona-2,5(10)- dien-17-one Reflux for 3 hours under nitrogen a mixture of 15 parts of 3-methoxy-13B-methyl B homogona-2,5(10)-dien- 17/3-ol, 500 parts by volume of toluene, 140 parts by volume of cyclohexanone and 7 parts of aluminum isopropoxide. Cool the refluxed material to room temperature, and then add thereto 20 parts by volume of water followed by 30 parts of sodium sulfate. Filter the thusobtained mixture and concentrate the filtrate to obtain the title compound as a solid.

(c) 17a-ethynyl-17/3-hydroxy-l3fl-methyl-B-homogon- 5 10) -en-3-one (|)H 0 B3 ---c ECH Add (in one portion) 12.2 parts of lithium-acetylideethylenediamine complex to a solution of 18.6 parts of 3-methoxy 13fl-methyl-B-homogona-2,5( l0)-dien-l7-one in 600 parts by volume of dimethyl acetamide. Pass acetylene for 2 hours (with continuous stirring) through the resulting solution. Then add 1000 parts by volume of ice water to the resultant and extract the obtained mixture with benzene. Evaporate the benzene extract to obtain 17u-ethynyl-3-rnethoxy 13p methyl-B-homogona- 2,5 (10)-dien-17;8-ol. Reflux the latter with a mixture of 50 parts of oxalic acid and parts by volume of 4:1 methanol/ water to obtain the title compound.

EXAMPLE 12 l7a-ethynyl-l7 3-hydroxy-l3 8-methyl-B-hon1og0na- 4-en-3-one Stir at room temperature for 3 hours a mixture of 28.3 parts of 17a-ethynyl-3-methoxy-13,8-methy1-B-homogona- 2,5 10-dien-17B-ol, 500 parts of methanol and 34 parts by volume of 11 N hydrochloric acid. Then dilute the resultant with brine before extracting same with chloroform. Wash and dry the chloroform solution and evaporate same to obtain the title compound.

EXAMPLE 13 (a) l7fl-hydroxy-13 3-methyl-B-homogon-4-en-3-one Stir for four hours at refluxing ammonia temperature a mixture of 5.4 parts of 3-methoXy-13-methyl-B-homogona- 1,3,5 (l)-trien-17fl-ol, 50 parts by volume of tetrahydrofuran, 200 parts by volume of liquid ammonia, 50 parts by volume of tert.-butyl alcohol and 1 part of lithium metal. Add to the resultant 50 parts by volume of methanol and then allow the ammonia to evaporate. Thereafter add thereto 200 parts by volume of water prior to concentration in vacuo, whereupon the intermediary, 3-methoxy- 13[3-methyl-B-homogona-2,5(10)-dien-17fl-ol, separates as an amorphous solid. Filter, wash thoroughly with water and dry said amorphous solid. Stir the thus-dried solid for 2.5 hours at room temperature with a mixture of 80 parts by volume of methanol, 8 parts by volume of water and parts by volume of concentrated hydrochloric acid. Thereafter dilute the resultant with 80 parts by volume of water to separate the title compound as a solid. Purify the thus-obtained titled compound by recrystallization from, e.g., diethyl ether-petroleum ether (9:1).

(b) 13 fi-methyll 7,8-propionyloxy-B-homogon-4-en-3-one o C 0 01120 H CH3 Admix 0.08 part of propionic acid anhydride with a solution of 0.2 part of 13,8-methyl-17B-hydroxy-B-homogon-4-en-3-one and 3 parts by volume of pyridine. Retain the resultant 4 hours at room temperature. Then pour the resulting mixture on ice water. Extract the resultant with chloroform to obtain the oily title compound.

EXAMPLE 14 13p,17a-diethyl-17p-hydroxy-B-homogona-4,9-dien-3-one Following the procedure of Example 2a, replace the 2-methylcyclopentane-1,3-dione with an equivalent of 2- ethylcyclopentane-1,3-dione to obtain the corresponding 13 ethyl 3 methoxy-8,l4,seco-B-homogona-1,3,5(), 9(11)-tetraene-l4,17-dione.

Following the procedure of Example 2b, replace the title compound of Example 2a with an equivalent of the thus-obtained l3-ethyl-3-methoxy-8,14-seco-B-homogona- 1,3,5 (10),9(1l)-tetraene-14,17-dione to obtain 13,8-ethyl- 3 methoxy B-homogona-1,3,5 (l0),8,l4-pentaen-l7-one, M.P. (89) 91 to 92 (after recrystallization from methanol).

Following the procedure of Example 3a, replace the title compound of Example 2b with an equivalent of 13/3- ethyl 3-methoxy-B-homogona-1,3,5 10) ,8,14-pentaen- 17 one to obtain 13;? ethyl-3-methoxy-B-homogona-1,3, 5(10),8,14-pentaen-17fl-ol.

Admix 0.07 part of acetic acid anhydride with a solution of 0.2 part of 13B-ethyl-3-methoxy-B-homogona- 1,3,5(10),8,14-pentaen-17B-ol and 3 parts by volume of pyridine. Retain the resultant at room temperature for four hours. Then pour the resulting mixture on ice water. Extract the resultant with chloroform to obtain the corresponding 17B-acetate, M.P. 142 to 143.

Following the procedure of Example 3b, replace the title compound of Example 3a with an equivalent of 13 8- 2.2 ethyl 3 methoxy-B-homogona-1,3,5(10),8,14-pentaen- 1713-01 to obtain 13 8-ethyl-3-methoxy-B-homogona-1,3, 5(10),8-tetraen-17B-ol.

Following the procedure of Example 30, replace the title compound of Example 3b with an equivalent of 13/3- ethyl 3-methoxy-B-homogona-1,3,5(10),8-tetraen-17Bol to obtain 13B ethyl-3-methoxy-B-hornogona-1,3,5(10)- trien-l7B-ol.

Following the procedure of Example 6b, replace the title compound of Example 6a with an equivalent of 13, 3- ethyl 3 methoxy-B-homogona-1,3,5(10)-trien-17B-ol to obtain l3(3-ethyl-3-methoxy-B-homogona-1,3,5 10)-trienl7-one.

Add 3.0 parts of -ethyl-S-methoxy-B-homogona- 1,3,5(10)-trien-17-one dissolved in 75 parts by volume of xylene to a Grignard mixture prepared from 1.23 parts of magnesium metal and 5.95 parts of ethyl bromide in 10 parts by volume of diethylether. Distill off the ether, and reflux the remainder for eighteen hours. After cooling the refluxed remainder to room temperature, add saturated (aq.) ammonium chloride solution thereto, and extract the resultant with chloroform to obtain 13B,17a-diethyl-3- methoxy-B-homogona-1,3,S 10)-trien- 1718-01.

Following the procedure of Example 9a, replace the title compound of Example 6a with an equivalent of 135, diethyl-3-methoxy-B-homogona-1,3,5(10)-trien-17/8- ol to obtain 13 B,17a-diethyl-3-methoxy-B-homogona-2, 5 1O -dien-17fi-ol.

Following the procedure of Example 9b, replace the title compound of Example 9a with an equivalent of 135, 17cc diethyl-3-rneth0Xy-B-hornogona-2,5(10)-di6I1-l7fl-Ol to obtain l35,17a-diethyl-17,8-hydroxy-B-homogon-5(l0)- en-3-one.

Add 0.7 part of pyridinium bromide perbromide to a solution of 0.58 part of 13B,17ot-diethyl-l7fl-hydroxy-B- homogon-5(10)-en-3-one in 8 parts by volume of pyridine at 7. Pyridine hydrobromide precipitates.

When the precipitation is considered to be complete, add thereto 25 parts by volume of Water. Separate by filtration the resulting precipitate (consisting of an intermediary dibromo compound). Wash the latter precipitate with water and then with small amounts of ice-cold ethyl acetate. Redissolve the thus-washed precipitate in 40 parts by volume of pyridine, and maintain the resulting solution at 30 for 2 hours. Add 100 parts by volume of water to the resultant and then extract same with chloroform. Evaporate the dried chloroform solution (extract) to obtain a foam. Admix the foam with diethyl ether to obtain the title compound as a colorless solid.

EXAMPLE 15 17a-chloroethynyl-13/3-ethyl-17fi-hydroxy-B-homogona- 4,8 .4),9-trien-3-one CH3 0H an Following the procedure of Example 6a, replace the 3 methoxy-13/3-methyl-B-homogona-1,3,5(10),8,14-pentaenll7fi-ol with an equivalent of 13fl-ethyl-3-methoxy- B-homogona-l,3,5(10),8,14-pentaen-17fi-ol (see Example 14) to obtain 13,8-ethyl-3-methoxy-B-homogona-1,3, 5(10),8(14)-tetraen-l7p-ol, M.P. (65)67 to 68, acetate M.P. (103)105 to 106.

Following the procedure of Example 9a, replace the title compound of Example 6a with an equivalent of 13fl-ethyl 3 methoxy-B-homogona1,3,5(10),8(14)-tetraen-17fl-ol to obtain 13fi-ethyl-3-methoxy-B-homogona- 2,5(10),8(14)-trien-17fi-ol.

Following the procedure of Example 9b, replace the title compound of Example 9a with an equivalent of l3fl-ethyl 3 methoxy-B-hmogona-2,5(10),8(14)-trien- 17/3-01 to obtain 1Sfl-ethyl-l7fl-hydroxy-B-homogona- 5(10),8(14)-dien-3-one.

Following the procedure of Example 9c, replace the title compound of Example 9b with an equivalent of 135- ethyl 17B hydroxy B hon1ogona-5(1O),8( l4)-dien-3 one to obtain 13B- ethyl-17fi-hydroxy-B-hon1ogona-4, 8 14) ,9-trien-3-one.

Following the procedure of Example 9d, replace the title compound of Example 9c with an equivalent of IBfl-ethyl-Ufl-hydroxy B homogona-4,8(14),9'trien-3- one to obtain 13fl-ethyl-B-hornogona-4,8(l4),9-triene- 3,17-dione.

Add, at 60, a solution of 0.7 part of trans-1,2- dichloroethylene in 2.0 parts by volume of diethyl ether to a sodamide mixture prepared from 0.3 part of sodium and parts of liquid ammonia. Maintain the resulting admixture at the reflux temperature of ammonia and add thereto a solution of 2.9 parts of 13,8-ethyl-B-homogona- 4,8(14),9-triene3,l7-dione and 15 parts by volume of THF.

After 90 minutes at pour the resultant into a mixture of ammonium chloride and ice, extract with diethyl ether, wash the ethereal extracts with dilute hydrochloric acid, aqueous sodium hydrocarbonate and water and dry over sodium sulfate. Chromatograph in an acid- Washed alumina to obtain the title compound.

What is claimed is:

1. A B-(6)-homogonene of the formula:

0 R1 ll 7 membered ring, and alltanoyl having from 2 to 4 carbon atoms;

R is a member of the group consisting of methyl, ethyl,

propyl and isopropyl;

any hydrogen bound to a member of the group consisting of C and C is in the Ot'pOSitlOIl, any hydrogen bound to C is in the fi-position, and any double bonds in the A, B, C and D rings are selected from the group consisting of ma o) A1,3,5(l0),8 1,3,s 1o),a,14 and 1,a,5 10),et14) 2. The compound according to claim 1 which is 3-rnethoxy 13,8 methyl-B-homogona-1,3,5(10),8,14-pentaenl7-one.

3. The compound according to claim 1 which is 3-methoxy 13fi methyl-B-homogona-1,3,5(10),8-tetraen-17- one.

4. The compound according to claim 1 which is 3-incthoxyl 3B-methyl-B-homogona-1,3,5 10)-trien-17-one.

5. The compound according to claim 1 which is 3-methoxy-13fl-methyl-B-homogona l,3,5(10),8(l4)-tetraenl7-one.

6. A compound according to claim 1 which is 3-methoxy 13,8 cthyl-B-homogona-1,3,5(10),8(14)-tetraen- 17-one.

7. The compound according to claim 1 which is 3-hydroxy 13p methyl-B-homogona-1,3,5(l0),8-tetraen-17- one.

8. The compound according to claim 1 which is 3-hydroxy-13/3-methyl-B-homogona-1,3,5(l0),8(14) tetraen- 17-one.

9. The compound according to claim 1 which is 3-hydroxy-13,8-n1ethyl-B-homogona-1,3,5(10)-trien-l7-one.

References Cited UNITED STATES PATENTS 3,291,836 12/1966 Tadanier et al. 260-586 H LEON ZITV ER, Primary Examiner G. A. SCHWARTZ, Assistant Examiner US. Cl. X.R. 260-479 R 

